Project Summary/Abstract: Childhood brain cancer is the most common solid tumor in children affecting approximately 2,500 children a year with an estimated 22,000 children living in the United States with a malignant brain tumor, which establishes this as an orphan disease. Current therapies for malignant childhood brain tumors including surgery, chemotherapy and radiation are very damaging to the developing brain of a child and can result in significant long-term brain injury and hormone dysfunction. Furthermore, approximately 25-30% of children with malignant brain cancer do not survive, and high-grade tumors that recur after current therapies are uniformly fatal. Therefore, novel therapies which target tumor cells while sparing normal cells are desperately needed. Oncolytic engineered herpes simplex virus (oHSV) therapy offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may be beneficial as an added therapy for curable tumors allowing for lower doses, and therefore, less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations (e.g. ?134.5 neurovirulence gene) in the virus that prevent infection in normal cells while maintaining the virus? ability to kill cancer cells. UAB has conducted three phase I trials of an engineered HSV G207, which has both copies of ?134.5 deleted and an insertional deletion of the ribonucleotide reductase gene for added safety, given alone and with a single small dose of radiation used to improve virus replication, in adults with recurrent high-grade brain tumors. In these trials, high doses (up to 3 x 109 plaque-forming units) were safely injected directly into the tumor or surrounding brain tissue without serious toxicities. While these trials were only designed to determine safety, many tumor responses were seen including two patients with complete (>5 years) responses. This trial data coupled with our preclinical data demonstrating that a variety of aggressive pediatric brain tumors are highly sensitive to oHSV strongly suggests that a pediatric oHSV trial would be a worthwhile endeavor. We propose to conduct a phase I clinical trial of G207 alone or combined with a single low dose of radiation in children with recurrent supratentorial brain tumors. Our primary goal is to determine safety. Our secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207 and on tumor genotypic and phenotypic features which may predict a response to oHSV.